Wilson's Disease is an inherited disease of copper accumulation which is fatal if untreated. The only established treatment (penicillamine) is itself extremely toxic. Thus, the need exists for alternative therapies. Our project is designed to fill this therapeutic gap. Our earlier work with zinc in sickle cell anemia showed that a particular regimen of zinc therapy causes copper deficiency. It occurred to us that zinc therapy might be useful in the treatment of Wilson's Disease. In work supported by this grant so far, we have succeeded in showing the feasibility of zinc treatment of Wilson's Disease. Thus, with the same regimen of zinc used in sickle cell patients we are able to put patients with Wilson's Disease into a negative copper balance while they are off penicillamine therapy. In the current application, we plan to further develop and fine tune this approach, and to expedite the spread of information on this therapeutic option across the country. Specifically, we plan to 1) establish the dose response relationship between oral zinc dose and copper balance in Wilson's patients; 2) To test whether administration of zinc with meals is less effective than administration between meals; 3) To study the effectiveness of a given oral zinc dose in relationship to variation in dietary copper intake; 4) To initiate long-term management in Wilson's patients with oral zinc therapy while developing monitoring techniques to establish adequacy of zinc treatment; 5) To gradually expand the number of patients under treatment by us and to increase the awareness of the medical community to this treatment approach; 6) To explore the effectiveness of zinc in comparison with penicillamine in initial decoppering of Wilson's patients; 7) Finally, to carry out certain animal experiments to develop further information on the mechanism of zinc/copper antagonism. If we accomplish the above aims, we should, by the end of the project, have a well-developed alternative therapy for Wilson's disease patients that is both non-toxic and effective. Further, we should understand reasonably well the mechanisms by which this therapy works.